Novel, potent P2–P3 pyrrolidine derivatives of ketoamide-based cathepsin K inhibitors

Barrett, David; Catalano, John G.; Deaton, David N.; Hassell, Anne M.; Long, Stacey T.; Miller, A. Whitman; Miller, Larry R.; Ray, John A.; Sámano, Vicente; Shewchuk, Lisa M.; Wells‐Knecht, Kevin J.; Willard, Derril H.; Wright, Laura

doi:10.1016/j.bmcl.2005.11.101

Cited by 20 publications

(7 citation statements)

References 11 publications

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“…One of the best studied immunosuppressant drugs, FK506 has an α-ketoamide, and it is a transition state analogue inhibitor of FK506 binding proteins (FKBPs) 5. α-Ketoamides have been used to inhibit several classes of proteases, such as serine proteases,6–10 cysteine proteases11–14 and HIV and FIV proteases 15…”

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confidence: 99%

Convergent Synthesis of α-Ketoamide Inhibitors of Pin1

Etzkorn

2010

Org. Lett.

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A convergent synthesis of α-ketoamide inhibitors of Pin1 is described. An α-hydroxyorthothioester derivative of Ser was reacted directly with an amine synthon. The reaction was catalyzed by HgO and HgCl 2 to form α-hydroxyamide. Thus, hydrolysis and coupling were combined in one step with 80% yield. Two diastereomers of a phospho-Ser-Pro α-ketoamide analogue were synthesized. The IC 50 values of 100 μM and 200 μM were surprisingly weak for Pin1 peptidyl-prolyl isomerase.α-Ketoamides have been widely used in developing inhibitors of peptidases,1 HDACs2 , 3 and peptidyl prolyl isomerases (PPIases). 4 One of the best studied immunosuppressant drugs, FK506 has an α-ketoamide, and it is a transition state analogue inhibitor of FK506 binding proteins (FKBPs).5 α-Ketoamides have been used to inhibit several classes of proteases, such as serine proteases,6 -10 cysteine proteases11 -14 and HIV and FIV proteases. 15 α-Ketoamides have an electron-deficient carbonyl due to the effect of the neighboring electronwithdrawing amide. α-Ketoamide containing inhibitors have been used to elucidate the mechanisms of enzymes, because they serve as transition state analogues to inhibit enzyme catalytic activity. This occurs for serine or cysteine proteases through the formation of a tetrahedral intermediate analogue (gem-diol or hemiketal) with the enzyme upon binding. 16 FK506, a macrolide with an α-ketoamide functional group, has a dihedral angle of 95° to 100°b etween the two carbonyl groups.5 NMR studies of a 13 C-labeled structure and a crystal structure of FK506 showed that the two carbonyls were orthogonal both in bound and unbound structures, indicating that FK506 acts as a "twisted amide" transition state analogue to inhibit FKBPs. 5 Pin1, a PPIase enzyme belonging to the parvulin family, specifically recognizes pSer/pThrPro containing substrates, and regulates many cellular events such as cell cycle progression, transformation, and cell proliferation. 17,18 Pin1 is overexpressed in many cancer cell lines, and plays an important role in oncogenesis. 19,20 Pin1 is a potential diagnostic and therapeutic anticancer target. [21][22][23] Thus, we are interested in developing potent and specific inhibitors of Pin1. 24,25 fetzkorn@vt.edu. Supporting Information Available: Experimental procedures, HPLC and spectroscopic data for compounds 1-10, and inhibition data for compound 1. This material is available free of charge via the Internet at http://pubs.acs.org. Since α-ketoamides are an important class of enzyme inhibitors, numerous synthetic methods have been reported, including: cyano ylide coupling, 26 transition-metal-catalysis, 27 amidation of α-keto acids with amines, 11,28 oxidation of α-hydroxyamides with Dess-Martin periodinane 6 or TEMPO, 29,30 and nucleophilic addition of a Grignard reagent to a Weinreb amide. 31 A solid-phase method for synthesis of α-ketoamides has been developed. 32 In this study, we have developed a convergent route to synthesize α-ketoamides by coupling a complex amine directly to an α-hydr...

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confidence: 99%

Convergent Synthesis of α-Ketoamide Inhibitors of Pin1

Etzkorn

2010

Org. Lett.

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“…Nitrogen based five membered heterocycle pyrrolidine, is a reassuring molecule for the design of newer drugs. It is well known from the literature that pyrrolidine, is a pharmaceutically active molecule and exhibits miscellaneous biological activities [1, 2, 3, 4, 5]. In addition, it is also apparent that certain compounds with benzylidene moiety in their structure are also important in the field of medicinal chemistry [6].…”

Section: Introductionmentioning

confidence: 99%

Synthesis, spectroscopic investigation, molecular docking and DFT studies of novel (2Z,4Z)-2,4-bis(4-chlorobenzylidene)-5-oxo-1-phenylpyrrolidine-3-carboxylic acid (BCOPCA)

Devi

Fatma

Shukla

et al. 2018

Heliyon

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The synthesized compound (2Z,4Z)-2,4-bis(4-chlorobenzylidene)-5-oxo-1-phenylpyrrolidine-3-carboxylic acid (BCOPCA) was characterised by Ultraviolet, FT-Infra Red, 1H, 13C Nuclear Magnetic Resonance and mass spectroscopy. The compound was further subjected to quantum chemical calculations at the level of density functional theory (DFT) using 6-31G (d,p) basis sets method with B3LYP and CAM-B3LYP hybrid functionals. The intramolecular interactions, polarizability, hyperpolarizability and nonlinear optical properties of the title compound were also incorporated in the study. The total first static hyperpolarizability (β0 = 19.477 × 10−30 and 16.924 × 10−30 esu) value was also computed and indicated the title molecule as an interesting forthcoming NLO material. The other thermodynamic properties (entropy, heat capacity and zero vibrational energy) were also discussed. The study also includes NBO computations, complete vibrational assignments, Mulliken charges, UV–Visible spectral analysis and HOMO–LUMO energies. The regions of low and high electron density were obtained from MESP and ESP maps. The calculated parameters for BCOPCA using aforementioned functions are harmonious with the experimental findings. The in-vitro antimicrobial activity and molecular docking studies of BCOPCA were also done and showed a good correlation.

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“…Review of the literature has shown that pyrrolidines are well known for their remarkable biological properties, such as anticonvulsant, 1,2 anti-HIV-1, 3 antitumor, 4 ketoamide-based cathepsin K inhibitor, 5,6 antimicrobial,…”

Section: Introductionmentioning

confidence: 99%

“…The pyrrolidine ring is found in large compounds demonstrating a significant range of biological activities. Review of the literature has shown that pyrrolidines are well known for their remarkable biological properties, such as anticonvulsant, 1,2 anti-HIV-1, 3 antitumor, 4 ketoamide-based cathepsin K inhibitor, 5,6 antimicrobial, 7−9 and sphingosine-1-phosphate (S1P) receptor agonist 10,11 activities.…”

Section: Introductionmentioning

confidence: 99%